Cowpox virus (CPXV) is distinguished from other orthopoxvirus (OPV) species by producing cytoplasmic A-type inclusion bodies and flattened pocks with a hemorrhagic center on the chorioallantoic membrane. CPXV is endemic to Western Eurasia and naturally infects a broad range of host species including domestic animals, and zoo animals, as well as humans. Infections in humans seem to increase in importance due to a changed epidemiology in the rodent reservoir hosts or in the biotype of the virus. Genetic characterization of CPXV isolates revealed differences which do not correlate with either host species or geographic origin. Phylogenetic analyses suggested a rodent-transmitted CPXV as an ancestor of all other OPV species. So far, only two strains from the UK and Russia are entirely sequenced. Sequence data from other strains isolated in Germany and Scandinavia are needed to better understand differences in virulence and severity of infection.